Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents

a technology of dihydroindolyl and dihydroindolyl, which is applied in the field of nuclear hormone receptors, can solve the problems of limiting the therapeutic potential of this approach, unphysiologically high levels, and ultimately decreasing, and achieves the effects of reducing the requirement for exogenous insulin, restoring blood glucose and triglyceride levels, and moderate complian

Inactive Publication Date: 2006-02-07
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the substantial side-effects limit the therapeutic potential of this approach.
The body continues to compensate by producing unphysiologically high levels of insulin, which ultimately decreases in later stage of disease, due to exhaustion and failure of pancreatic insulin-producing capacity.
These compounds, however, suffer from side effects, including rare but severe liver toxicity (as seen with troglitazone).
They also increase body weight in patients.
In addition, such compounds may also lower LDL cholesterol, decrease blood pressure and counteract inflammatory atherosclerosis.

Method used

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  • Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents
  • Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents
  • Indolyl and dihydroindolyl derivatives, their manufacture and use as pharmaceutical agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

{5-[4-(2-Methoxy-ethyl)-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid

a] 5-(tert-Butyl-dimethyl-silanyloxy)-1H-indole

[0178]A solution of 5 g (37.55 mmol) of 5-hydroxy-indole, 6.13 g (39.4 mmol) of tert-butyldimethylsilyl chloride and 5.37 g (68.1 mmol) of imidazole in 50 ml DMF was stirred for 20 h at RT. The reaction mixture was taken up in ether, washed with 1N HCl and water and the ether solution was then concentrated under reduced pressure, to give 9.4 g (quant.) of clean 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole.

[0179]MS: 248.1 (M+H)+.

b] [5-(tert-Butyl-dimethyl-silanyloxy)-indol-1-yl]-acetic acid ethyl ester

[0180]To a solution of 9.2 g (37.18 mmol) 5-(tert-butyl-dimethyl-silanyloxy)-1H-indole and 4.79 ml (40.9 mmol) ethyl bromoacetate in 140 ml of DMF was added 36.35 g (111.5 mmol) of cesium carbonate. The reaction mixture was stirred for 3 h at RT, taken up in ether and then washed with 1N HCl and water. The ether phase was concentrated under re...

example 2

{5-[4-Methyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid

a] 2-[1-Ethoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester

[0195]A solution of 5 g (38.42 mmol) 3-oxo-butyric acid ethyl ester, 12.78 ml (76.84 mmol) triethyl orthoformate in 80 ml acetic anhydride was boiled for 2.5 h at 150° C. The reaction mixture was concentrated under reduced pressure at 90° C. to provide 6.84 g of almost pure 2-[1-ethoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester.

[0196]MS: 186.9 (M+H)+.

b] 4-Methyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester

[0197]To a solution of 2 g (7.67 mmol) 4-trifluoromethyl-benzamidine HCl in 30 ml ethanol was added 0.76 g (7.67 mmol) sodium tert-butoxide and 1.43 g (7.67 mmol) 2-[1-ethoxy-meth-(E,Z)-ylidene]-3-oxo-butyric acid ethyl ester. The reaction was stirred at RT over night and for 1 h under reflux. After the solvent was removed under reduced pressure, the residue was taken up in ether and washed with 1N ...

example 3

{5-[4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-indol-1-yl}-acetic acid

a] (E,Z)-2-Cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester

[0207]A solution of 10 g (70.34 mmol) 3-cyclopropyl-3-oxo-propionic acid methyl ester, 23.4 ml (140.68 mmol) of triethyl orthoformate in 100 ml acetic anhydride was refluxed at 150° C. for 5 h. The reaction mixture was concentrated at 95° C. under reduced pressure to give 14.35 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester.

[0208]MS: 199.3 (M+H)+.

b] 4-Cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine-5-carboxylic acid ethyl ester

[0209]To a solution of 4.74 g (18.19 mmol) 4-trifluoromethyl-benzamidine HCl in 50 ml of ethanol was added 1.82 g (18.19 mmol) of sodium tert-butoxide. After 2 min, 3.61 g of crude (E,Z)-2-cyclopropanecarbonyl-3-ethoxy-acrylic acid methyl ester was added and the reaction mixture was stirred over night at RT. The ethanol was removed under reduced pressure, the residue taken...

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Abstract

This invention relates to compounds of the formula wherein one of R6, R7 and R8 is and X, Y1 to Y4, R1 to R14 and n are as defined in the description, and to all enantiomers and pharmaceutically acceptable salts and / or esters thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and / or prevention of diseases which are modulated by PPARδ and / or PPARα agonists.

Description

SUMMARY OF THE INVENTION[0001]The present invention is concerned with novel indolyl or dihydroindolyl derivatives of the formula wherein[0002]R1-9 are as described herein.[0003]It has been found that compounds of formula I are useful as lipid modulators and insulin sensitizers. In particular, compounds of formula I are PPAR activators.BACKGROUND OF THE INVENTION[0004]Peroxisome Proliferator Activated Receptors (PPARs) are members of the nuclear hormone receptor superfamily. The PPARs are ligand-activated transcription factors that regulate gene expression and control multiple metabolic pathways. Three subtypes have been described which are PPARα, PPARδ (also known as PPARβ), and PPARγ. PPARδ is ubiquitously expressed. PPARα is predominantly expressed in the liver, kidney and heart. There are at least two major isoforms of PPARγ. PPARγ1 is expressed in most tissues, and the longer isoform, PPARγ2 is almost exclusively expressed in adipose tissue. The PPARs modulate a variety of physi...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07D401/04C07D401/14C07D403/02C07D401/12C07D403/12
CPCC04B35/632C07D403/12C07D401/12A61P3/04A61P3/06A61P3/10A61P7/02A61P9/10A61P9/12A61P15/00A61P29/00A61P35/00
Inventor ACKERMANN, JEANAEBI, JOHANNESBINGGELI, ALFREDGRETHER, UWEHIRTH, GEORGESKUHN, BERNDMAERKI, HANS-PETERMEYER, MARKUSMOHR, PETERWRIGHT, MATTHEW BLAKE
Owner F HOFFMANN LA ROCHE & CO AG
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